Project Summary/Abstract The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in the IRF5 region are associated with a wide-range of immune-mediated diseases, included IBD. We found that IRF5 is the single most important genetic determinant of the inter- individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, how IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA IC&IIC). Key to IBD pathogenesis is the ability of myeloid cells to clear microbes; however, how IRF5 regulates clearance of both resident and pathogenic intestinal microbes is not known (SA III). Multiple cell subsets can contribute to intestinal immune dysregulation, and limited in vivo studies in IRF5-/- mice have also demonstrated a role for IRF5 in T cell outcomes, with decreased Th1 differentiation in lupus model systems. However, whether IRF5 regulates T cell outcomes in a T cell-intrinsic (SA I) or T cell-extrinsic (SA II) manner is not known, including in intestinal tissues. We hypothesize that IRF5 will contribute to multiple immune cell functions essential in intestinal immune homeostasis in vivo through its role in both myeloid and T cell subsets, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens. We further hypothesize that IRF5 IBD-associated polymorphisms will modulate the identified roles for IRF5 in these pertinent immune outcomes. We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis